This invention relates to an improved process for the preparation of 3-methyl-2-[2-chlorosulfinyl-4-oxo-3-acylamido-1-azetidinyl]-3-butenoic acid esters represented by the following structural formula. ##STR1## wherein acyl represents the acyl residue of a carboxylic acid and R.sub.1 is a carboxy protecting group.
The above esters are referred to herein for convenience as 2-chlorosulfinyl azetidin-4-ones. These azetidinones are useful intermediates in the process for preparing 7-acylamido-3-exomethylenecepham-4-carboxylic acid ester sulfoxides.
Kukolja et al. described, in U.S. Pat. No. 3,843,682 issued Oct. 22, 1974, the preparation of diacylamido chlorosulfinylazetidinones by reacting a 6-diacylamido penicillin sulfoxide ester, for example, p-nitrobenzyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate sulfoxide, with sulfuryl chloride in an inert hydrocarbon solvent such as benzene.
Kukolja, in co-pending application Ser. No. 673,017 filed Apr. 2, 1976 now U.S. Pat. No. 4,081,440, describes the conversion of 6-acylamido penicillin sulfoxide esters to the acylamido 2-chlorosulfinyl azetidin-4-one compounds represented by the above formula by reacting the penicillin sulfoxide with a N-chloro halogenating agent, such as N-chlorosuccinimide, in the presence of an alkylene oxide, such as propylene or butylene oxide. The latter Kukolja process is distinguished from that described in the above-cited U.S. Pat. No. 3,843,682 wherein only 6-diacylamido penicillin ester sulfoxides were converted to the 2-chlorosulfinylazetidinones. In contrast, the latter Kukolja process employs a 6-monoacylamido penicillin sulfoxide ester which previously had not been converted to an azetidinone-type compound.
Later, Ta-Sen Chou in co-pending application Ser. No. 696,674 filed June 16, 1976 now U.S. Pat. No. 4,075,203 described an improved process, over that described by Kukolja, for preparing the acylamido-2-chlorosulfinylazetidin-4-ones on a large scale. The process improvement comprises using calcium oxide in conjunction with one of the alkylene oxides described by Kukolja to obtain enhanced yields particularly in large scale preparations of the 2-chlorosulfinyl compounds.
In co-pending application Ser. No. 673,036 filed Apr. 2, 1976, Kukolja describes the process for converting acylamido 2-chlorosulfinylazetidin-4-ones by a Lewis acid-Friedel-Crafts catalyzed intramolecular cyclization to the 7-acylamido-3-exomethylenecepham-4-carboxylic acid ester sulfoxides represented by the following formula. ##STR2##
This invention comprises an improvement in the conversion of a 6-acylamido penicillin sulfoxide ester to the corresponding 3-acylamido 2-chlorosulfinylazetidin-4-one intermediate. Previously, the 6-monoacylamido penicillin sulfoxide employed in the above-described processes had the .beta.-configuration represented by the following partial structural formula. ##STR3##
In the above formula of the .beta.-configuration, the sulfoxide oxygen is forward or above the plane.
According to the improved process of this invention, a 6-acylamido-2,2-dimethylpenam-3-carboxylic acid ester sulfoxide wherein the sulfoxide group has the .alpha.-configuration as represented by the following structural formula ##STR4## is employed in the above-described process to provide the 2-chlorosulfinylazetidin-4-one intermediate in enhanced yields. The 2-chlorosulfinylazetidin-4-one is converted to a 3-exomethylenecepham sulfoxide ester in improved yields of higher purity material than is obtained in the prior process employing the penicillin sulfoxide ester having the .beta.-configuration.
The proposed course of the above-described process involves initially the thermolysis of the penicillin thiazolidine ring to form the ring-opened sulfenic acid according to the following reaction scheme. ##STR5## The sulfenic acid intermediate then reacts with an N-chloro halogenating agent, for example, N-chlorosuccinimide to provide the 2-chlorosulfinylazetidin-4-one according to the following reaction scheme. ##STR6## The sulfinyl chloride is then reacted with a Lewis acid-Friedel-Crafts type catalyst, such as stannic chloride, to effect the intramolecular cyclization with formation of the 7-acylamido-3-exomethylenecepham-4-carboxylic acid ester sulfoxide having the .beta.-configuration as shown in the following reaction scheme. ##STR7##
It has been discovered that the penicillin .alpha.-sulfoxide undergoes facile cleavage to the sulfenic acid at a lower temperature than does the .beta.-sulfoxide. Further, it has been discovered that the N-chloro halogenating agent reacts instantaneously with the sulfenic acid to provide the sulfinyl chloride. The use of the .alpha.-sulfoxide allows the process to be carried out at lower temperatures and over a shorter period of time than does the use of the corresponding penicillin .beta.-sulfoxide. For example, penicillin V .alpha.-sulfoxide ester undergoes conversion in 2 hours to the sulfinyl chloride when the process is carried out at a temperature of about 78.degree. C. In contrast penicillin V .beta.-sulfoxide ester requires a temperature of about 110.degree. C. for conversion to the sulfinyl chloride in about 2 hours. Since the process can be carried out faster decomposition products occurring over the longer reaction times with the sulfinyl chloride are diminished. For example, the sulfinyl chloride can react with the starting sulfoxide to form several .beta.-lactam ring opened side products. Or it will disproportionate to give sulfonyl chloride and the unstable sulfenyl chloride which will further decompose. The avoidance of the longer reaction times required with the penicillin .beta.-sulfoxide greatly reduces these side reactions and thus provides higher yields of the intermediate sulfinyl chlorides which are reflected in higher yields of the cyclized 7-acylamido-3-exomethylenecepham-4-carboxylic acid ester .beta.-sulfoxide in a high state of purity.